This invention relates to a pharmaceutical composition for relieving side-effects, particularly dysfunction of the kidneys caused by the administration of platinum-containing drugs such as cisplatinumum (cisplatin, cis-diamminedichloroplatinum (II)).
The platinum-containing drugs including cisplatinum are potent carcinostatics employed in many clinical fields, and known to have marked effects on orchioncus, bladder cancer, pyeloureteral tumor, prostatic cancer, ovarian cancer, cancer of the head and neck, lung cancer, and the like.
Cisplatinum, however, has serious side effects including kidney dysfunction. These side effects, which have been known ever since the development of cisplatinum, are dose limiting factors in the administration of cisplatinum which significantly delimits its clinical utility.
The kidney dysfunction caused by the administration of cisplatinum is histopathologically a disorder of proximal uriniferous tubule near its S.sub.3 segment, which results in acute turbulorrhexis or necrosis of the uriniferous tubule. The disorder of the proximal uriniferous tubule may clinically be detected by increased values of blood urea nitrogen (BUN), creatinine, fractional excretion of Na (FENa), .gamma.-glutamyltranspeptitase (.gamma.-GTP), and N-acetyl-.beta.-D-glucosaminidase (NAG) in urine.
Accordingly, there has been a strong clinical need for the development of means for relieving the kidney dysfunction caused by cisplatinum.
Japanese Patent Application Kokai No. 60-28928 discloses that fosfomycin can relieve the side effects caused by the administration of carcinostatics including platinum-containing agents such as cisplatinum, anthracycline-based carcinostatics, and nitrosourea-based carcinostatics. In Example 2, fosfomycin significantly suppressed development of the kidney dysfunction caused by cisplatinum as evidenced by reduced increase of BUN and creatinine values in a group wherein a combination of cisplatinum and fosfomycin is administered over a group wherein cisplatinum is solely administered.
Japanese Patent Application Kokai No. 62-106021 discloses administering elastase together with cisplatinum to relieve the side effects including the kidney dysfunction caused by the cisplatinum.
It is also reported that cisplatinum is capable of activating hyaluronidase which participates in the development of kidney dysfunction and various hyaluronidase inhibitors including sodium azulenesulfonate which are effective in relieving kidney dysfunction.
All of the substances used in the above-mentioned prior art documents are foreign and exogenous to the human body. Fosfomycin is a substance produced by a microorganism, is Streptomyces fragiae. Elastase is a protein generally derived from porcine pancreas. Hyaluronidase-inhibiting substances are also foreign to the human body. Accordingly, there is a need for developing a less-dangerous endogenous agent for relieving kidney dysfunction caused by cisplatinum.
The inventors of the present invention have made various investigations to find reliable means for avoiding kidney dysfunction, which is clinically the most serious and troublesome side effect caused by the administration of cisplatinum. After such an investigation, the inventors have found that ulinastatin (urinastatin), which is a human urinary trypsin inhibitor, is markedly effective for relieving the side effects, particularly the kidney dysfunction caused by cisplatinum.